Neurotrophic Factor Signaling in the Pathogenesis of HIV-associated Depression: Cohort and Mechanistic Studies

HIV 相关抑郁症发病机制中的神经营养因子信号传导：队列和机制研究

• 批准号: 10369264
• 负责人: SARAH LOFGREN
• 金额: $ 19.56万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369264
• 关键词: Affect; Affective; Automobile Driving; Biological Markers; Biological Models; Body Fluids; Brain; Brain-Derived Neurotrophic Factor; Caring; Cells; Cerebrospinal Fluid; Clinical; Clinical Data; Cognition; Cognitive; Data; Data Collection; Depressed mood; Depression screen; Disease Pathway; Ensure; Evaluation; Exhibits; Functional disorder; Future; HIV; HIV Infections; HIV-associated neurocognitive disorder; Human; Individual; Infection; Infusion procedures; Machine Learning; Maintenance; Mental Depression; Mus; National Institute of Mental Health; Neural Pathways; Neuronal Plasticity; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Outcome; Outpatients; Pathogenesis; Pathway interactions; Patient Self-Report; Peptides; Phenotype; Play; Population; Prevalence; Process; Prospective cohort; Proteins; Proteomics; Publications; Quality of life; Research Domain Criteria; Rewards; Role; Sampling; Signal Pathway; Signal Transduction; Social Interaction; Stem cell transplant; Sterility; Sucrose; Symptoms; Tail Suspension; Testing; Time; Tissues; Validation; Viral; Water; Work; antiretroviral therapy; case control; cohort; depression model; depressive symptoms; epidemiology study; follow-up; humanized mouse; immune reconstitution; improved; mortality; mouse model; neurocognitive test; neuroinflammation; neuron development; neurotrophic factor; preference; protein expression; psychosocial; receptor; resilience; response; social; symptomatology; therapy resistant; treatment adherence

Abstract Neurotrophic Factor Signaling in the Pathogenesis of HIV-associated Depression: Cohort and Mechanistic Studies Depression in people with HIV is known to worsen HIV outcomes as well as quality of life. Prior studies have shown Brain Derived Neurotrophic Factor (BDNF) is pivotal in neuron development and maintenance and important in depression. To better understand the pathophysiology of depression in HIV, we desire to use proteomics to further study the BDNF pathways in pre- existing CSF samples from people with HIV and then do a proof-of-concept test in a murine HIV model of depression. We have access to cerebrospinal fluid from a cohort of outpatients with HIV collected in a study of HIV-associated Neurocognitive Disorders with CSF and clinical data collection at 0 and 2 years. The evaluation included neurocognitive testing and depression screening with the center for epidemiological studies depression (CESD). We plan to do discovery and validation proteomics with focus in the validation proteomics for the BDNF pathway. We will use a machine-learning analysis plan comparing our proteomics findings with the CESD generally and on an item-level basis as well as cognitive evaluations using the NIMH Research Domain Criteria (RDoC) constructs with focus on Loss, Reward Valuation, and Cognition. We plan to do this analysis first cross-sectionally and then further validate by comparing longitudinally. We hypothesize CSF neurotrophic factor BDNF with neuroinflammatory markers are associated with depressive symptoms; strength of association with depressive symptoms will vary within RDoC domains with persistent neuroinflammation closely tied to ongoing symptoms. We plan to use our findings from proteomics in an HIV murine model of depression with focus on the BDNF pathways. We plan to acquire humanized mice and infect half with HIV. We will evaluate them for depression and then inject half with a BDNF antagonist and evaluate again with standard depression testing. We hypothesize the treated mice to exhibit more signs of depression than untreated mice (less sucrose preference, less social interaction, less immobile time) as BDNF improves resilience and neuroplasticity. Successful completion will yield impactful data on the BDNF pathways and could discover additional targets for treatment of HIV-associated depression.

抽象的 艾滋病毒相关抑郁的发病机理中的神经营养因子信号传导：队列和 机械研究 众所周知，艾滋病毒患者的抑郁症会恶化艾滋病毒的结果和生活质量。事先的 研究表明，脑衍生的神经营养因子（BDNF）在神经元发展中是关键的 维护，在抑郁症中很重要。更好地了解 艾滋病毒的抑郁症，我们希望使用蛋白质组学进一步研究前bdnf途径 来自艾滋病毒患者的现有CSF样品，然后在鼠类艾滋病毒中进行概念验证测试 抑郁型模型。 我们可以从研究中收集的HIV的一系列门诊病人获得脑脊液 与CSF和临床数据收集在0和2的艾滋病毒相关的神经认知障碍 年。评估包括与中心的神经认知测试和抑郁筛查 用于流行病学研究抑郁症（CESD）。我们计划进行发现和验证 蛋白质组学与BDNF途径的验证蛋白质组学有关。我们将使用一个 机器学习分析计划将我们的蛋白质组学发现与CESD进行比较 在项目层面以及使用NIMH研究领域进行认知评估的基础上 标准（RDOC）构建，重点是损失，奖励估值和认知。我们打算做 该分析首先是横截面，然后通过纵向比较进一步验证。我们 假设具有神经炎症标记的CSF神经营养因子BDNF是相关的 有抑郁症状；与抑郁症状相关的强度在内 具有持续性神经炎症的RDOC结构域与持续的症状紧密相关。 我们计划在艾滋病毒的抑郁症模型中使用蛋白质组学的发现，重点 在BDNF途径上。我们计划获取人源化的小鼠，并用艾滋病毒感染一半。我们将 评估它们的抑郁症，然后将一半注入BDNF拮抗剂，然后再次评估 进行标准抑郁测试。我们假设处理过的小鼠表现出更多的迹象 抑郁症比未经治疗的小鼠（蔗糖的偏好较少，社交互动较少，固定不动 时间）随着BDNF提高弹性和神经可塑性。 成功完成将在BDNF途径上产生有影响力的数据，并可能发现 治疗艾滋病毒相关抑郁症的其他靶标。